Molecular Tools May Offer Clues To Reducing Risks of Birth Defects

By GINA KOLATA

Published: May 23, 1995

VIRTUALLY every scientist who has ever studied birth defects has been haunted by the same question: why are some babies born with devastating defects when their mothers have taken drugs like the sedative thalidomide or the acne drug Accutane or the epilepsy drug dilantin, while others with the same exposure are unscathed?

And, for years, the question seemed almost unanswerable. Some thought it was a matter of timing. If a woman took thalidomide during the first three months of her pregnancy, when her baby's limbs were forming, the baby would be born with the flipper-like limbs that so unforgettably marked thalidomide children. If she took the drug later, the baby would be unaffected. It could just be the bad luck of exposing a fetus to a teratogen, or birth defect-inducing substance, at exactly the wrong time.

But Accutane, for one, stays in the body for months after a woman takes it. And even though it is one of the most potent teratogens known, "a sledgehammer," says Dr. Lewis Holmes of Massachusetts General Hospital, it affects only about a third to a half of fetuses exposed to it.

Nor does the timing argument seem supported by what is known about dilantin and other anticonvulsant drugs that epileptic women must take throughout their pregnancies and that can cause a variety of birth defects. The risk of having a baby with birth defects is doubled in women who take dilantin or other anticonvulsants, but, still, just 6 to 12 percent of babies are affected. Why these babies and not the others? Timing also fails to explain why just 20 to 30 percent of diabetic women with blood sugar levels that are poorly controlled have babies with birth defects.

But now, armed with the techniques of molecular biology and molecular genetics, researchers are starting to discover particular attributes of women and of fetuses that can spell disaster when a fetus is exposed to a teratogen. In some cases, it is a gene in the fetus that determines if it is vulnerable. In other cases, it is a gene active in the mother that puts her fetus at risk.

This new direction, birth defect researchers say, is reviving a field that had seemed moribund.

Recently, scientists have found an answer to the mystery of why some, but not most, women whose diets are deficient in folic acid have babies with neural tube defects like spina bifida. Others found a fetal gene that may determine whether a baby is born with a cleft palate when its mother smokes. Still others are investigating enzyme defects that may determine whether anticonvulsants, or alcohol, cause birth defects.

"It's tremendously exciting," said Dr. Allan Wilcox, the chief of the epidemiology branch at the National Institute of Environmental Health Sciences. "I've been studying reproductive problems for some time and I never did anything with birth defects because it was hard to think of anything that hadn't been done over and over again." But now, Dr. Wilcox said, he is seeing endless opportunities and is eagerly joining the growing field.

Dr. Allen Mitchell, a pediatric epidemiologist at the Sloan School of Epidemiology of Boston University, called the new work "very exciting" and said it might have profound implications for the way teratogenic drugs were regulated.

"Until now, we've banned them, like thalidomide, or ignored them, like dilantin," he said. But the drugs are often necessary and neither option is desirable.

When the new research comes to fruition, Dr. Mitchell said, he could imagine a middle ground. "You could take this to almost a science fiction scenario," he said. "At age 12, every woman would have a screen done by her physician and that screen would say: you have a gene that should you ever take drug X will put you at risk of having a baby with a birth defect."

The work on neural tube defects was directed by Dr. James Mills, the chief of the pediatric epidemiology section at the National Institute of Child Health and Human Development. These common, and particularly devastating birth defects, which involve the brain and spinal cord, were recently shown to be associated with deficiencies of the vitamin folic acid. Women who had poor diets, eating few green vegetables, for example, were most susceptible. And those who took folic acid supplements early in pregnancy, when the neural tube normally zips closed, reduced their risk of having a baby with the defects by 50 to 70 percent.

But, Dr. Mills said, "We don't think it's just dietary." For example, he said, "if you look in parts of Africa, where the diet is just horrendous, they don't have many neural tube defects." Babies born to Celtic women have a high incidence of the defects, as do babies born to Hispanic women. But only rarely do the defects occur in black babies.

To see if there is a genetic reason why some women's babies are more susceptible than others, Dr. Mills and his colleagues studied women in Dublin, collecting blood at the time of their first prenatal visit and then following the women through their pregnancies to see which gave birth to babies with neural tube defects. Finally, they compared the medical histories of the 81 women in the group whose babies had birth defects with those of 323 women randomly selected from the group who had normal babies.